Development of new cancer chemoprevention agents: role of pharmacokinetic/pharmacodynamic and intermediate endpoint biomarker monitoring.
Recently, several promising strategies have been advanced for improving the efficiency of new agent development. These include pharmacokinetic/pharmacodynamic (PK/PD) and intermediate endpoint biomarker (IEB) monitoring. Here, we review their essential role as practical tools for guiding the evaluation of agents for cancer chemoprevention (CP) and provide examples of CP agents that utilize these approaches. Several important categories of IEBs are delineated, including histologically based (intraepithelial neoplasias and nuclear morphometry). The use of select IEBs combined with a Bayesian method for clinical trial monitoring for rapid identification of ineffective or promising agents is discussed. The similarities between IEB and TDM are described. Finally, we present future tools for enhanced monitoring of CP agents that will impact on laboratory medicine and are also applicable to many other drug classes, e.g., laser capture microdissection and cDNA chip microarrays that assess gene expression patterns of precancerous and cancerous lesions.
Lieberman
R
R
Chemoprevention Branch, National Cancer Institute, Rockville, MD 20852, USA. Liebermr@dcpcepn.nci.nih.gov
Crowell
J A
JA
Hawk
E T
ET
Boone
C W
CW
Sigman
C C
CC
Kelloff
G J
GJ
D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D016587:Antimutagenic Agents / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000975:Antioxidants / Q000627:therapeutic use; D001499:Bayes Theorem; D014408:Biomarkers, Tumor / Q000627:therapeutic use; D018890:Chemoprevention; D003201:Computers; D016903:Drug Monitoring; D006801:Humans; D009369:Neoplasms / Q000453:epidemiology; D010599:Pharmacokinetics
D000893:Anti-Inflammatory Agents; D016587:Antimutagenic Agents; D000970:Antineoplastic Agents; D000975:Antioxidants; D014408:Biomarkers, Tumor